The Effect of Everolimus on Subependymal Giant Cell Astrocytoma (SEGA) in Children with Tuberous Sclerosis Complex

Objective: Subependymal Giant Cell Astrocytomas (SEGAs) are slow-growing glioneuronal tumors typically found around the ventricles of the brain, particularly near the foramen of Monro in 15%-20% of patients with tuberous sclerosis complex (TSC). Surgical resection is the standard treatment for these symptomatic tumors. The mTOR inhibitor everolimus can be regarded as an alternative treatment for SEGAs due to the complications of surgery. The present study primarily aimed to specify the effect of everolimus on SEGA volume change before and after treatment. The secondary objective was to determine the effect of this drug on renal angiomyolipoma (AML), skin lesions, and seizures in TSC patients. Materials & Methods: This pre- and post-treatment clinical trial was performed on 14 children (eight females and six males with a mean age of 10 years) previously diagnosed with TSC based on the diagnostic criteria. The subjects received oral everolimus at a dose of 3 mg/m2 for at least six months. Results: Half of the patients had more than 30% of volume loss in SEGA, and in 28.5% of them, a ≥ 50% reduction in SEGA volume was observed (P=0.01). Moreover, 92.9% of the patients had a ≥ 50% decrease in the frequency of seizures (P=0.000). The response rate in AML and skin lesions was 14.2% and 50%, respectively. Conclusion: Everolimus significantly reduced the seizure frequency and SEGA volume in the subjects; hence, it can be used as a potential alternative treatment for symptomatic SEGA in TSC patients.


Introduction
Tuberous sclerosis, a genetic disorder with autosomal dominant inheritance, occurs in approximately 1/5800 live births (1). This disease is currently known as tuberous sclerosis complex (TSC) due to its probable effects on one or several other vital organs in addition to the central nervous system. This condition is characterized by the presence of hamartomas in many organs, especially the brain (such as cortical tubers, subependymal giant cell astrocytomas (SEGAs), and subependymal nodules), eyes, kidneys, skin, and heart (2, 3).
Its clinical manifestations vary from mild cases with exclusive affection of the skin to life-threatening complications, such as hydrocephalous. The involvement of different organs is dependent on age; for instance, cardiac lesions usually occur in younger individuals, even in the fetal period, and renal lesions are often detected after adolescence.
About one million people are affected by this disorder around the world (4).
Neurologic manifestations in TSC patients range from normal intelligence and the absence of seizures to intellectual disability and drug-resistant epilepsy. With a prevalence of 80-90%, the seizure is the most common neurologic sign in these patients (5)(6)(7). In these people, the seizure is mostly

Conclusion
Everolimus significantly reduced the seizure frequency and SEGA volume in the subjects; hence, it can be used as a potential alternative treatment for symptomatic SEGA in TSC patients. Recent studies (11,12) have indicated the impact of the mammalian target of rapamycin (mTOR) inhibitor on SEGA regression in TSC patients.

Keywords
Based on the results of these studies, the Food and Drug Administration (FDA) has approved the application of this agent in TSC patients who are not suitable candidates for surgical resection (13).
This approval has entailed the expansive usage of this medicine, and there is even consensus concerning the application of mTOR in patients with growing SEGA and no clinical signs.
Everolimus is a rapamycin analog that reduces tumor volume through inhibiting mTOR in TSC patients (10). The present study primarily was done to specify the effect of mTOR on SEGA volume change before and after treatment. The secondary objective of this study was to determine the effect of this drug on renal angiomyolipoma (AML), skin lesions, and seizures in TSC patients.
To our knowledge, there is no comprehensive data regarding the safety and efficacy of this drug in TSC children in Iran.

Materials & Methods
This prospective open-label, pre-, and post-  In some studies, a reduction of 30% or more and no new lesions during treatment were considered as the criteria for positive medication effects (14).
However, in most studies, at least a 50% decrease was regarded for the positive effect of the drug on SEGA. In this study, we considered a reduction of ≥ 30% as a relative response and ≥ 50% as a favorable response. Seizure frequency was specified by AEDs remained unchanged, and everolimus was used as adjunctive, and baseline seizure frequency was assessed. A decrease of 50% or more in the frequency of seizures was considered favorable for this medicine.
In renal AML, a reduction of 50% or more relative to AML volume in the baseline in the absence of new AML ≥1 cm and no AML-related bleeding of grade ≥ 2 was considered as a positive effect.

Results
We evaluated 17 patients with SEGA in the present study. The treatment was ceased in one of the patients due to severe oral aphthous ulcers, and two patients left the study three months after its initiation. Ultimately, 14 patients (eight females and six males) were enrolled in this study for at least six months. In three patients (21.4 %), SEGA volume loss of 30% to less than 50% was noted; however, a reduction rate of 50% or more in SEGA volume was observed in 4 out of 14 (28.5%) patients (Fig.1). SEGA progression was detected in one patient (Case # 2, Table 1). The decrease in SEGA volume was statistically significant (P<0.01).
The medication was observed to be effective in seizure control. More specifically, the seizure was reduced by 90% and 50%-90% in 10 and three cases, respectively (P <0.001) ( Table 2). three patients; upon the emergence of these signs, the treatment was stopped and resumed after their resolution. However, one subject exhibited serious oral aphthous lesions and was excluded from the study. By stopping the drug, oral aphthous was resolved.    dose (21). Seemingly, skin lesion also responds to low doses of everolimus.
Mizuguchi et al. (32) and Hwang et al. (33) observed notable improvement in behavior and autistic symptoms in patients but we did not control it by questionnaire.

Limitations of this study
No genetic studies for mutations of TSC1 and TSC2, small sample size, and short follow-up due to high cost of the drug, no checking for drug level due to unavailability to do in our center.

In Conclusion
According to the findings of this study, everolimus significantly affected the multisystem manifestation of TSC. More specifically, this drug reduced the seizure frequency and SEGA volume in TSC patients, which can be a safe alternative treatment for TSC patients with SEGA.